Antagonists used for positron emission tomographic (PET) studies of dopamine D2/D3 receptors do not distinguish between the high-affinity (HA) and low-affinity (LA) states of the receptors. We and others have now accomplished imaging only the HA-state of dopamine D2/D3 receptors using aminotetralin-based and apomorphine-based PET radiotracers. These studies confirm that some of the D2/D3 receptors in the striatum of the living rodent and monkey are present in the HA-state. The ability to image and reliably quantitate the amount of receptors present in the HA-state has a number of applications. These include: (a), the study of etiology of disease states such as schizophrenia, manic depression and Parkinson's disease; (b). study of dopamine release since dopamine now competes with a more sensitive PET radiotracer that is bound only (or predominantly) to the HA-state; (c). study of therapeutic drugs that may shift population of affinity states, from HA- to LA-state. Our goal is this application is two-fold: 1. Develop and evaluate agents that are suitable for HA-state imaging of striatal and extrastriatal receptors; and 2. Evaluate HA-state radiotracers that will be able to discriminate between D2 and D3 receptor subtypes. We have optimized 5- hydroxyaminotetralins for imaging dopamine D2 receptors which has resulted in the development of 18F-5- OH-FPPAT as a suitable imaging agent. We propose to optimize radiosynthesis of the more active isomer S-18F-5-OH-FPPAT and carry out in vitro and in vivo binding properties of both R- and S-isomers. The high- affinity agent 11C-PPHT will be studied for extrastriatal HA-states. Both, R- and S-isomers will be evaluated. Quantitative microPET studies to measure amphetamine-induced dopamine release in striatal and extrastriatal regions will be carried out. In order to direct the tetralins to the D3 receptor, the 7-hydroxy analogs of FPPAT and PPHT will be investigated. Specifically we will synthesize R- and S-isomers of 18F-7- OH-FPPAT and 11C-7-OH-PPHT that may have potential as D3 selective agents. Fluorine-18 analog of PPHT, 18F-FPPHT (both 5- and 7-hydroxy) will also be prepared for extrastriatal imaging of HA-states. Pharmacological characterization of these agents using D3 cell lines, brain homogenates, autoradiographic studies, D2 and D3 receptor knock-out mice microPET studies will be carried out. Finally PET studies will be carried out in monkeys with these agents to demonstrate HA-state binding and receptor subtype selectivity. [unreadable] [unreadable] [unreadable]